Molecular Mechanics Of Cyclic Antibiotics Biology Essay




The development of new antibacterial therapeutic agents capable of halting microbial resistance is a chief pursuit in clinical medicine.[1] In an effort to address this threat of microbial antibiotic resistance, researchers have pursued several strategies, one being the development of peptide based antibiotics.[2] These antibiotic peptides exhibit a fast and lethal mode of action that is quite different from the mode of action of other synthetic antibiotics, making peptide antibiotics attractive therapeutic targets.[2]

Currently, more than 500 antimicrobial peptides have been isolated from a wide range of organisms. Peptides are classified based on their structure of which there are four major classes: β-sheet, α-helical, loop and extended peptides [3], with the first two classes being the most common in nature. [4] The β-sheet peptides represent a highly diverse group of molecules at the level of primary structure. Despite such differences, these peptides share common features, including amphipathic composition, with distinct hydrophobic and hydrophilic surfaces. [5] Both the α-helical and β-sheet peptides are amphiphilic in nature. [6] β-sheet peptides are mainly cyclic, and can be subdivided into two subgroups: those containing disulfide bonds, such as tachyplesin and those that do not, such as gramacidine S [7, 8] and the tyrocidines.

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Cyclic β-sheet peptides

Peptides containing disulfide bridges

Cyclic β-sheet peptides can be constrained by disulfide cross-links or backbone cylization. Tachyplesins, polyphemusins, bactenecins, and protegrins are examples of disulfide-constrained antibiotic peptides.

Peptides lacking disulfide bridges

An understanding of the key features of the secondary and tertiary structures of the antimicrobial peptides and their effects on bactericidal and hemolytic activity can aid the rational design of improved analogs for clinical use.[9] Studies on a broad range of peptides reveal two important requirements for antimicrobial activity, (1) a cationic charge and (2) an induced amphipathic conformation. [4]

Michael R. Yeaman; Nannette Y. Yount. Mechanisms of antimicrobial peptide action and resistance. Pharmacological reviews. 2003; 55:27 - 55 .

Cationicity is undoubtedly important for the initial electrostatic attraction of antimicrobial peptides to negatively charged phospholipids membranes of bacteria and other micro organisms, and mutual electroaffinity likely confers selective antimicrobial targeting relative to host tissues. The fact that bacterial membranes are rich in the acidic phospholipids PG, PS, and CL confers their overall negative charge. Moreover, LPS and teichoic or teichuronic acids of Gram-negative and Gram-positive bacteria, impart additional negative charge to the surfaces of these respective organisms.

Michael R. Yeaman; Nannette Y. Yount. Mechanisms of antimicrobial peptide action and resistance. Pharmacological reviews. 2003; 55:27 - 55 .

The amphipathicity is characterized by a variable number of β-strands, with relatively few or no helical domains, organized to create both polar and non-polar surfaces. These β-strands are frequently antiparallel, and are stablized by a series of disulfide bonds, with as many as eight cysteins in some peptides [ eg plant defensis(sitaram and nagaraj 1999) and muscel mytilins (dimarcq 1998)],or by cyclization of the peptide backbone (e.g protegrins, gramicidin, or θ-defensins). The conformational rigidity observed in many β-sheet antimicrobial peptides in aqueous solution may also promote multimerization, limiting exposure of hydrophobic facets to hydrophilic environments A number of β-sheet peptides have been shown to exist as dimmers in aqueous solution

The proposed mechanism by which antimicrobial peptides perturb target membranes involve amphipathicity and hydrophobic moment. For example, insertion of the hydrophobic peptide face into the lipid bilayer, and association of the charged arginine side chains with polar lipid head groups, relies upon three-dimensional separation of hydrophobic and charge. Once associated with the membrane, the amphipathic nature of β-sheet peptides likely enables their formation of transmembrane channels.Several models have been proposed to explain the exact mechanism by which these peptides may form and traverse the channel;however the precise conformation adopted by such peptides in the hydrophobic membrane environment remains to be determined.

Three approaches are currently being used to develop antibiotics. The first involve modification of existing peptides (and presumably also isolation of novel peptides from nature and modification of these). For example, the streptogramins are a family of cyclic peptides discovered in the 1950s, which are quite potent but rather insoluble. Recent work has resulted in two water-soluble, semi synthetic streptogramins, dalfopristin and quinupristin. A second rather exciting approach involves the modular nature of synthesis of the antibiotics. Schneider et al discovered that one can put together a novel combination of peptide synthesis modules and arrive at a novel structure. Thus there is great potential for obtaining significant chemical diversity in the backbone amino acids or their modifications, and a combinatorial approach to generating diversity (i.e. mixing and matching modules) is possible. The third approach is to use these structures as templates for chemical synthesis and diversity. Gramicidin S and tyrocidine A are examples of this approach. Variants of gramicidin S with altered ring size, charge amino acid sequences, hydrophobicity, etc have been constructed and shown to have greater selectivity for bacteria than for mammalian cells.

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Proposed mechanism of action

An overview of the interaction of peptides with Gram-negative bacteria is as shown in the fig below. The initial association of peptides with the bacterial membrane occurs through electrostatic interactions between the cationic peptide and the LPS in the outer membrane leading to membrane perturbation. It has also been shown that cationic peptides have a higher affinity for LPS in the outer leaflet of the outer membrane of Gram-negative bacteria than do native divalent cations such as Mg2+ and Ca2+. [10] Passage across the outer membrane is proposed to occur by self promoted uptake. According to this hypothesis, unfolded cationic peptides are proposed to associate with the negatively charged surface of the outer membrane and either nuetralize the charge over a patch of the outer membrane, creating cracks through which the peptide can cross the outer membrane (A), or actually bind to the divalent cation binding sites on LPS and disrupt the membrane (B). Once the peptide has transited the outer membrane, it will bind to the negatively charged surface of the cytoplasm ic membrane, created by the head groups of phosphatidylglycerol and cardiolipin, and the amphipathic peptide will insert into the membrane interface (the region where the phospholipid headgroups meet the fatty acyl chains of the phospholipid membrane) (C). It is not known at which point in this process the peptide actually folds into its amphipathic structure (i.e during transit across the outer membrane or during insertion into the cytoplasmic membrane). Many peptide molecules will insert into membrane inteface and are proposed to then either aggregate into micelle-like complex which spans the membrane (D) or flip flop under the influence of large transmembrane electrical potential gradient (approximately 140mV) (E). The micelle-like aggregates (D) are proposed to have water associated with them, and this provides channels for the movement of ions across the membrane and possibly leakage of larger water-soluble molecules. These aggregates would be variable in size and life time and will dissociate into monomers that maybe disposed at either side of the membrane. The net effect of (D) and (E) is that some monomers will be translocated into the cytoplasm and can dissociate from the membrane and bind to cellur polyanions such as DNA and RNA (F) [10


Understanding the relationship between structure and function of these peptides has been a challenging task. This study is limited to the investigation of the structures, self assembly, specifically the dimerization and aggregation of two cyclic peptides: tyrocidine A and tyrocidine C in aqueous solution as well as in decane. We also investigate the binding of Ca(II) ions to tyrocidine C.

1. Michael A. Marques, Diane M. Citron, Clay C. Wang. Development of Tyrocidine A analogues with improved antibacterial activity. Bioorganic & Medicinal Chemistry 2007; 15:6667- 6677

2. Hans G. Holman. Peptide antibiotics and their role in innate immunity 1995;13:61-92

3. Robert E. W. Hancock, R. Lehrer . Cationic peptides: a new source of antibiotics.

4. Jon-Paul S.Powers, Robert E. W. Hancock. The relationship between peptide structure and antibacterial activity. Peptides 2003; 24:1681- 1691

5. Tushar K. Chakraborty, Dipankar Koley, Rapolu Ravi, Viswanatha Krishnakumari, Ramakrishnan Nagaraj, Ajit C. Kunwar. Synthesis, conformational analysis and biological studies of cyclic cationic antimicrobial peptides containing sugar amino acids. J.Org. Chem 2008; 73:8731 - 8744

6. Andreu David, Luis Rivas. Animal antimicrobial peptides: an overview. Biopolymers 1998; 47:415 - 433